Additive and/or synergistic effects of 5 alpha-dihydrotestosterone, dexamethasone, and triiodo-L-thyronine on induction of proteinases and epidermal growth factor in the submandibular gland of hypophysectomized mice.

The effects of androgen, glucocorticoid, and thyroid hormones on levels of proteinase isozymes and epidermal growth factor (EGF) in the submandibular glands of hypophysectomized (Hypox) mice were investigated. Total proteinase activity in males was decreased by hypophysectomy and increased by single or combined injection of the three hormones into these mice. 5 alpha-Dihydrotestosterone (DHT) had the strongest effect, and dexamethasone (Dex) the least. By isoelectric focusing, proteinases extracted from the submandibular gland of untreated male and female mice were fractionated into four isozymes with pI values of 4.8 (proteinase-F), 5.8 (proteinase-D), 6.2 (proteinase-A), and 10.0 (proteinase-P). In Hypox mice (both sexes), there was only a single isozyme, proteinase-F. Proteinase-D, -A, and -P were induced in the submandibular gland of Hypox males by injections of DHT, Dex, and/or T3; the percent ratio of activity of each of these isozymes induced by these hormones, given either singly or in combination, was almost parallel among the three isozymes. Synergistic effects were observed between T3 and Dex, and additive effects between T3 and DHT. The increase in proteinase isozyme activities by concomitant injections of T3 and Dex was about 2 times more than the additive values. The changes in proteinase-F upon hormone injection were complicated. In females, the enzyme activity was decreased by hypophysectomy and increased by DHT administration. In males, on the other hand, it was increased by hypophysectomy and suppressed by T3 or T3 plus steroid hormones. The EGF level in the submandibular gland was decreased to about 1/800th (males) or 1/90th (females) of its normal level by hypophysectomy. Its level in the Hypox animal was greatly increased by all three hormones, given singly or in combination. Synergism was also observed between T3 and steroid hormones; DHT plus T3 and T3 plus Dex induced EGF 6 times and 9 times, respectively, more than the additive values. These values were much greater than those for the induction of proteinase-D, -A, and -P by combined injections of T3 and steroids. The present results suggest that the genes coding for proteinase-A, -D, and -P are located close to each other and that the onset of their expression may be controlled by the same regulatory mechanism. By contrast, the gene for proteinase-F may be mapped to a different locus or regulated differently. The mechanism of induction of EGF by T3, DHT, and Dex appears to be similar to but not completely the same as that for proteinase-D, -A, and -P.